Metastatic cancer poses a formidable treatment challenge. This application is based on our efforts to develop new technology to deal with treatment of invasive and metastatic cancer. We developed a treatment of glioblastomas (GMBs) that closely mimic the human disease with regard to the diffuse invasiveness of the tumors. The treatment modality is a novel nanosystem we have used to obtain an impressive degree of control over these tumors. The nanosystem consists of a pro-apoptotic peptide made highly potent by coupling it to the surface of nanoparticles, which are guided to the tumors by a tumor-homing peptide. This homing peptide also causes internalization of the particles into the target cells. It further has the unique property of delivering the payload to the mitochondria, which are the target of the pro-apoptotic peptide. Additionally, the iron oxide component served as an MRI contrast agent. The promising treatment results were achieved in the face of a complete failure of a number of other attempted treatments in the GBM models. More recently, we have shown that breast cancer is also a good target for the nanosystem. Both the GBM and breast cancer results have brought up the puzzling paradox that while we are able to destroy most of the conventional tumor vasculature, the mice ultimately succumb to the disease in the aggressive tumor models. Preliminary results suggest that the treated tumors develop some kind of alternative circulation that makes them resistant to further treatment with the nanosystem. We propose to characterize this alternative circulation and develop ways of targeting it for destruction. These studies will increase the understanding of how tumors survive anti-angiogenic and vascular disrupting treatments that destroy the conventional tumor vasculature. The results may also yield more efficacious treatments for cancers, including cancer types that are essentially resistant to all currently available treatments.